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image of Ursolic Acid Inhibits Triple-Negative Breast Cancer Progression by Modulating the FGFR1/AKT/ERK Pathway: Evidence from Network Pharmacology andExperimental Validation

Abstract

Introduction

Ursolic acid (UA) exhibits antitumor activity; however, its effects and mechanisms on triple-negative breast cancer (TNBC) cells are not well understood. The present study aimed to explore the anti-TNBC mechanisms of UA by network pharmacology and experimental validation.

Methods

TNBC cell lines MDA-MB-231 and BT-549 cells were treated with UA. A CCK-8 assay was performed to detect cell growth, while flow cytometry assessed cell cycle arrest and apoptosis. The underlying mechanism and potential targets of UA for TNBC treatment were investigated by network pharmacology, including PharmMapper database, GO, KEGG enrichment, and PPI analysis. The protein expressions and phosphorylation levels of FGFR1, AKT, and ERK were measured by western blot. Pull-down assay, cellular thermal shift assay (CETSA), and molecular docking were used to analyze the interaction between UA and FGFR1. Xenograft models were established to examine the effect of UA on TNBC tumor growth.

Results

UA effectively reduced cell viability, induced apoptosis, and arrested cell cycle in TNBC cells. Moreover, UA significantly regulated the expression of Bcl-2 and Bax to induce apoptosis. The results of network pharmacology and western blot suggested that UA reduced FGFR1/AKT/ERK pathway. Furthermore, pull-down, CETSA, and molecular docking results revealed that UA directly bound to FGFR1. In the xenograft model, UA inhibited the growth by suppressing FGFR1.

Discussion

In this study, we employed network pharmacology and experimental approaches to elucidate the mechanism of UA on TNBC. The results demonstrated that UA targeted FGFR1 to inhibit TNBC mediating FGFR1/AKT/ERK pathway.

Conclusions

Our findings demonstrate that UA inhibits the FGFR1/AKT/ERK pathway by directly targeting FGFR1, thereby suppressing TNBC progression and supporting its potential as a therapeutic agent for TNBC treatment.

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2025-08-21
2025-12-24

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References

  1. Siegel R.L. Giaquinto A.N. Jemal A. Cancer statistics, 2024. CA Cancer J. Clin. 2024 74 1 12 49 10.3322/caac.21820 38230766
    [Google Scholar]
  2. Derakhshan F. Reis-Filho J.S. Pathogenesis of triple-negative breast cancer. Annu. Rev. Pathol. 2022 17 1 181 204 10.1146/annurev‑pathol‑042420‑093238 35073169
    [Google Scholar]
  3. Karim A.M. Eun Kwon J. Ali T. Jang J. Ullah I. Lee Y.G. Park D.W. Park J. Jeang J.W. Kang S.C. Triple-negative breast cancer: epidemiology, molecular mechanisms, and modern vaccine-based treatment strategies. Biochem. Pharmacol. 2023 212 115545 10.1016/j.bcp.2023.115545 37044296
    [Google Scholar]
  4. MacDonald I. Nixon N.A. Khan O.F. Triple-negative breast cancer: A review of current curative intent therapies. Curr. Oncol. 2022 29 7 4768 4778 10.3390/curroncol29070378
    [Google Scholar]
  5. Chen C.J. Shih Y.L. Yeh M.Y. Liao N.C. Chung H.Y. Liu K.L. Lee M.H. Chou P.Y. Hou H.Y. Chou J.S. Chung J.G. Ursolic acid induces apoptotic cell death through aif and endo g release through a mitochondria-dependent pathway in NCI-H292 human lung cancer cells in vitro. In Vivo 2019 33 2 383 391 10.21873/invivo.11485 30804116
    [Google Scholar]
  6. Yang X. Li Y. Jiang W. Ou M. Chen Y. Xu Y. Wu Q. Zheng Q. Wu F. Wang L. Zou W. Zhang Y.J. Shao J. Synthesis and biological evaluation of novel ursolic acid derivatives as potential anticancer prodrugs. Chem. Biol. Drug Des. 2015 86 6 1397 1404 10.1111/cbdd.12608 26077799
    [Google Scholar]
  7. Yeh C.T. Wu C.H. Yen G.C. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c‐Jun N ‐terminal kinase, Akt and mammalian target of rapamycin signaling. Mol. Nutr. Food Res. 2010 54 9 1285 1295 10.1002/mnfr.200900414 20352621
    [Google Scholar]
  8. Beenken A. Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat. Rev. Drug Discov. 2009 8 3 235 253 10.1038/nrd2792 19247306
    [Google Scholar]
  9. Ornitz D.M. Itoh N. The fibroblast growth signaling pathway. Wiley Interdiscip. Rev. Dev. Biol. 2015 4 3 215 266 10.1002/wdev.176 25772309
    [Google Scholar]
  10. Dienstmann R. Rodon J. Prat A. Perez-Garcia J. Adamo B. Felip E. Cortes J. Iafrate A.J. Nuciforo P. Tabernero J. Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors. Ann. Oncol. 2014 25 3 552 563 10.1093/annonc/mdt419 24265351
    [Google Scholar]
  11. Turner N. Pearson A. Sharpe R. Lambros M. Geyer F. Lopez-Garcia M.A. Natrajan R. Marchio C. Iorns E. Mackay A. Gillett C. Grigoriadis A. Tutt A. Reis-Filho J.S. Ashworth A. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010 70 5 2085 2094 10.1158/0008‑5472.CAN‑09‑3746 20179196
    [Google Scholar]
  12. Waddell N. Pajic M. Patch A.M. Chang D.K. Kassahn K.S. Bailey P. Johns A.L. Miller D. Nones K. Quek K. Quinn M.C.J. Robertson A.J. Fadlullah M.Z.H. Bruxner T.J.C. Christ A.N. Harliwong I. Idrisoglu S. Manning S. Nourse C. Nourbakhsh E. Wani S. Wilson P.J. Markham E. Cloonan N. Anderson M.J. Fink J.L. Holmes O. Kazakoff S.H. Leonard C. Newell F. Poudel B. Song S. Taylor D. Waddell N. Wood S. Xu Q. Wu J. Pinese M. Cowley M.J. Lee H.C. Jones M.D. Nagrial A.M. Humphris J. Chantrill L.A. Chin V. Steinmann A.M. Mawson A. Humphrey E.S. Colvin E.K. Chou A. Scarlett C.J. Pinho A.V. Giry-Laterriere M. Rooman I. Samra J.S. Kench J.G. Pettitt J.A. Merrett N.D. Toon C. Epari K. Nguyen N.Q. Barbour A. Zeps N. Jamieson N.B. Graham J.S. Niclou S.P. Bjerkvig R. Grützmann R. Aust D. Hruban R.H. Maitra A. Iacobuzio-Donahue C.A. Wolfgang C.L. Morgan R.A. Lawlor R.T. Corbo V. Bassi C. Falconi M. Zamboni G. Tortora G. Tempero M.A. Gill A.J. Eshleman J.R. Pilarsky C. Scarpa A. Musgrove E.A. Pearson J.V. Biankin A.V. Grimmond S.M. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015 518 7540 495 501 10.1038/nature14169 25719666
    [Google Scholar]
  13. Lánczky A. Győrffy B. Web-based survival analysis tool tailored for medical research (KMplot): Development and implementation. J. Med. Internet Res. 2021 23 7 e27633 10.2196/27633 34309564
    [Google Scholar]
  14. Yin L. Duan J.J. Bian X.W. Yu S. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020 22 1 61 10.1186/s13058‑020‑01296‑5 32517735
    [Google Scholar]
  15. Singh R. Letai A. Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 2019 20 3 175 193 10.1038/s41580‑018‑0089‑8 30655609
    [Google Scholar]
  16. Wan S.Z. Liu C. Huang C.K. Luo F.Y. Zhu X. Ursolic acid improves intestinal damage and bacterial dysbiosis in liver fibrosis mice. Front. Pharmacol. 2019 10 1321 10.3389/fphar.2019.01321 31736766
    [Google Scholar]
  17. Gu G. Barone I. Gelsomino L. Giordano C. Bonofiglio D. Statti G. Menichini F. Catalano S. Andò S. Oldenlandia diffusa extracts exert antiproliferative and apoptotic effects on human breast cancer cells through ERα/Sp1‐mediated p53 activation. J. Cell. Physiol. 2012 227 10 3363 3372 10.1002/jcp.24035 22213398
    [Google Scholar]
  18. Kim G.D. Ursolic acid decreases the proliferation of MCF-7 cell-derived breast cancer stem-like cells by modulating the ERK and PI3K/AKT signaling pathways. Prev. Nutr. Food Sci. 2021 26 4 434 444 10.3746/pnf.2021.26.4.434 35047440
    [Google Scholar]
  19. Zhang R. Zhu X. Bai H. Ning K. Network pharmacology databases for traditional chinese medicine: review and assessment. Front. Pharmacol. 2019 10 123 10.3389/fphar.2019.00123 30846939
    [Google Scholar]
  20. Wang R. Liu H. Shao Y. Wang K. Yin S. Qiu Y. Wu H. Liu E. Wang T. Gao X. Yu H. Sophoridine inhibits human colorectal cancer progression via targeting MAPKAKP2. Mol. Cancer Res. 2019 17 12 2469 2479 10.1158/1541‑7786.MCR‑19‑0553 31575657
    [Google Scholar]
  21. van der Noll R. Leijen S. Neuteboom G.H.G. Beijnen J.H. Schellens J.H.M. Effect of inhibition of the FGFR–MAPK signaling pathway on the development of ocular toxicities. Cancer Treat. Rev. 2013 39 6 664 672 10.1016/j.ctrv.2013.01.003 23434072
    [Google Scholar]
  22. Chen L. Zhang X. Liu G. Chen S. Zheng M. Zhu S. Zhang S. Fibroblast growth factor 3 promotes spontaneous mammary tumorigenesis in Tientsin albino 2 mice via the FGF3/FGFR1/STAT3 pathway. Front. Oncol. 2023 13 1161410 10.3389/fonc.2023.1161410 37496658
    [Google Scholar]
  23. Feng S. Shao L. Castro P. Coleman I. Nelson P.S. Smith P.D. Davies B.R. Ittmann M. Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors. Oncotarget 2017 8 4 6179 6192 10.18632/oncotarget.14049 28008155
    [Google Scholar]
  24. Cheng Q. Ma Z. Shi Y. Parris A.B. Kong L. Yang X. FGFR1 overexpression induces cancer cell stemness and enhanced Akt/Erk-ER signaling to promote palbociclib resistance in luminal a breast cancer cells. Cells 2021 10 11 3008 10.3390/cells10113008 34831231
    [Google Scholar]
  25. Park H.S. Jeoung N.H. Autocrine motility factor secreted by HeLa cells inhibits the growth of many cancer cells by regulating AKT/ERK signaling. Biochem. Biophys. Res. Commun. 2020 525 3 557 562 10.1016/j.bbrc.2020.02.135 32113681
    [Google Scholar]
  26. Kong S. Cao Y. Li X. Li Z. Xin Y. Meng Y. MiR‐3116 sensitizes glioma cells to temozolomide by targeting FGFR1 and regulating the FGFR1/PI3K/AKT pathway. J. Cell. Mol. Med. 2020 24 8 4677 4686 10.1111/jcmm.15133 32181582
    [Google Scholar]
  27. Chang J. Liu X. Wang S. Zhang Z. Wu Z. Zhang X. Li J. Prognostic value of FGFR gene amplification in patients with different types of cancer: a systematic review and meta-analysis. PLoS One 2014 9 8 e105524 10.1371/journal.pone.0105524 25171497
    [Google Scholar]
  28. Xie F. Lu H.Y. Zheng Q.Q. Qin J. Gao Y. Zhang Y.P. Hu X. Mao W.M. The clinical pathological characteristics and prognosis of FGFR1 gene amplification in non-small-cell lung cancer: a meta-analysis. OncoTargets Ther. 2016 9 171 181 10.2147/OTT.S91848 26793001
    [Google Scholar]
  29. Liu G. Chen T. Ding Z. Wang Y. Wei Y. Wei X. Inhibition of FGF‐FGFR and VEGF‐VEGFR signalling in cancer treatment. Cell Prolif. 2021 54 4 e13009 10.1111/cpr.13009 33655556
    [Google Scholar]
  30. Navid S. Fan C.O. Flores-Villanueva P. Generali D. Li Y. The fibroblast growth factor receptors in breast cancer: From oncogenesis to better treatments. Int. J. Mol. Sci. 2020 21 6 2011 10.3390/ijms21062011 32188012
    [Google Scholar]
  31. Chen Z. Tong L. Tang B. Liu H. Wang X. Zhang T. Cao X. Chen Y. Li H. Qian X. Xu Y. Xie H. Ding J. C11, a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor, suppresses breast cancer metastasis and angiogenesis. Acta Pharmacol. Sin. 2019 40 6 823 832 10.1038/s41401‑018‑0191‑7 30487650
    [Google Scholar]
  32. Santolla M.F. Talia M. Maggiolini M. S100A4 Is Involved in Stimulatory Effects Elicited by the FGF2/FGFR1 Signaling Pathway in Triple-Negative Breast Cancer (TNBC) Cells. Int. J. Mol. Sci. 2021 22 9 4720 10.3390/ijms22094720 33946884
    [Google Scholar]
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Ursolic Acid Inhibits Triple-Negative Breast Cancer Progression by Modulating the FGFR1/AKT/ERK Pathway: Evidence from Network Pharmacology andExperimental Validation
Bentham Science Publishers ; https://doi.org/10.2174/0118715206379579250722053647
/content/journals/acamc/10.2174/0118715206379579250722053647
/content/journals/acamc/10.2174/0118715206379579250722053647
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  • Article Type:     Research Article
Keywords: apoptosis ; triple-negative breast cancer ; fgfr1/akt/erk pathway ; network pharmacology ; cell cycle ; Ursolic acid

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